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2014-01-08T10:29:00.000-08:00

Sedative Hypnotics

2010-12-03T04:15:00.001-08:00

These include 3 types of drugs;

Benzodiazepines
Barbiturates
Miscellaneous agents

Benzodiazepines (BZ)

These were introduced in 1960.
These are most commonly used.

Mechanism of Action

It is based on GABA receptors stimulation.
GABA (amino acid) binds with receptors and chloride channels open and there is influx of chloride ions which leads to hyper-polarization of membrane and sedation occurs. This is normal phenomenon.
Benzodiazepines facilitate this mechanism by facilitating the binding of GABA receptors to their receptors which lead to sustained hyper-polarization.
It is dose dependent effect;
Low dose…. Sedation
High dose… Hypnosis
If GABA concentration is low, BZ are not able to perform their action because these only facilitate binding not the release of GABA.

Classification of BZ

Their classification is based on duration of activity;

Short Acting BZ

Drugs with half life less than 5 hours and include;
Midazolam
Triazolam

Medium Acting BZ

Drugs with half life b/w 5-24 hours and include
Alprazolam
Lorazepam

Long Acting BZ

Drugs with half life greater than 24 hours and include
Diazepam
Chlorodiazep

Flumazenil

This drug is used to treat the toxicity of BZ b/c it is antagonist of BZ.

Effects of BZ

These act as anti-convulsants and also reduce the anxiety.
These are poor analgesic but good muscle relaxant.
Effects on CVS and respiratory systems are negligible.

Therapeutic Uses

Sedative and hypnotic
Anti-convulsants
Used for sleep disorders
Pre-anesthetic
Midazolam can be used as anesthetic agent.

Problem

If used for longer duration, problem of dependency occurs and abrupt withdrawal leads to anxiety, convulsions and other withdrawal symptoms.

Barbiturates

These are synthesized from urea and malonic acid.
Urea and malonic acid combine to form Barbituric acid.
Barbituric acid is not having hypnotic property.
When hydrogen at 5^th carbon in Barbituric acid is replaced by other substitutes, then these have hypnotic property.
If thiaurea is used instead of Urea, Thiobarbiturates are formed which are good lipid soluble. Sodium salts of Thio-barbiturates are used as injectable anesthetics.
These are having dose dependent effect;
Low dose…Sedation
High dose…Hypnosis
Higher dose…..Anesthesia
In BZ, higher dose do not lead to anesthesia.
So Barbiturates are used as general anesthetics.

Classification of Barbiturates

Their classification is also based on duration of activity;

Ultra-short acting

Drugs with half life b/w 10-30 minutes and include;
Thiopental
Thiobarbitone
hexobarbitone

Short acting

Drugs with half life b/w 30min-3hours and include;
Pentobarbitone
Secobarbitone

Medium acting

Drugs with half life b/w 3-6 hours and include;
Butobarbitone
Amylobarbitone

Long acting

Drugs with half life more than 6 hours and include;
Phenobarbitone
Mephobarbitone

Effects of Barbiturates

Sedation, hypnosis and anesthesia
Anti-convulsants
Poor analgesics
Higher doses can lead to respiratory failure and death. To treat this, respiratory center stimulants (Doxapram) are used.

Therapeutic Uses

Sedative, hypnotic and anesthetic
Anti-convulsants (Phenobarbitone, Primidone)

Miscellaneous Drugs

Chloral Hydrate through oral route can be given.
Chlorobutanol
Bromides
Ethyl Alcohol
Cannabis (Bhang)

Classification of Anesthetics

2010-12-03T04:09:00.000-08:00

There are two bases for classification of general anesthetics;

Physical
Route of Administration

Inhalant Anesthetics

Anesthetics which are inhaled, reach the alveoli, exchanged with arterial blood and distributed to different body parts especially Brain are called as inhalant anesthetics.

There are 3 important phases of anesthesia;

Induction
Maintenance
Recovery

Factors Affecting Anesthesia

Blood Gas Solubility
Potency
Gas Lipid Solubility

Blood Gas Solubility

More the solubility of the inhalant anesthetic, it will take more time to saturate and more time to depress the Brain and vice versa.
So, more the solubility of an inhalant anesthetic, it will take more time for induction and recovery of Anesthesia.

Low solubility inhalant anesthetic

Low the solubility of inhalant anesthetic, minor change in concentration will lead to greater change in depth of anesthesia.
Low solubility inhalant anesthetics include Nitrous oxide, Ether, Halothene, Fluorine.

Potency

It is the ability of the drug to depress the CNS. It is measured by MAC value.
MAC (Minimum Alveolar Concentration)
Minimum concentration in alveoli which can induce anesthesia in 50% of the patients
Lower the MAC value, more potent is the anesthetic agent.
MAC value of drugs is in following order;
Methoxy Fluorine < Halothene < Isofluorine < Ether < Nitrous Oxide

Gas Lipid Solubility

If a drug is more lipids soluble, it will take more time for induction and recovery. Its value is in the following order;
Nitrous Oxide > Isofluorine > Halothene > Ether > Methoxy Fluorine

Examples of Inhalant Anesthetics

Volatile

Chloroform, Ether mixture, Halothene, Isofluorine, N-fluorine, Methoxy fluorine, vinyl ether

Gaseous

Cyclopropaine, Nitrous Oxide

Chloroform

In 1847, it was used as general anesthetic. It is still in use.
In 1846, ether was used as general anesthetic.
If it is used externally, it is rubifacient.
If it is used by oral route, it has anti-spasmatic (Muscle relaxant), anti-zymatic (stop production of gas) and carminative (removal of gases) effects.
If inhaled, it induces anesthesia. It induces rapid induction. It gives good analgesia and muscle relaxation.
It can also cause irritation in alveoli. So, Bronchial and salivary secretions are increased and there is possibility of pneumonia. So, along with this drug, Head should be down and atropine can also be used.
It also induces hepato-toxicity, myocardial sensitization to epinephrine. So, there are chances of Cardiac Arrhythmia.
It is non-explosive and non-inflammable.

Ether

It increases bronchial and salivary secretions when inhaled due to irritation.
Good analgesic and relaxant
Induction is slow.
It is inflammable and explosive.
Low toxicity problem. So, mixture of chloroform and ether is best combination as an anesthetic.
ACE (alcohol, chloroform and ether mixture) in the ratio of 1:2:3 is also available.

CycloPropaine

Inflammable, explosive
Good analgesic and relaxant
Can cause myocardial sensitization

Nitrous Oxide (Laughing Gas)

It induces light anesthesia (pleasant induction).
Used in humans
Low toxicity
Rapid induction and recovery

Injectable Anesthetics

These are of two types;

Depressants

Barbiturates (thiopental, pentobarbitone, secobarbitone, hexobarbitone)
Chloral-hydrate
Etomidate
Midazolam

Dissociative

Phencyclodine
Ketamine
Tiletamine
These induce superficial sleep. There is good analgesia, poor relaxation and poor hyporeflexia.
Myotonia, reflexes and amnesia is also present.
Eyelids remain open and there are chances of corneal ulceration. So, use some ointment to close eyes.
Use some tranquilizers or sedatives
Ketamine and Xylazine combination is best.
Ketamine is used in veterinary practice.

Examples of Injectable Anesthetics

Thiobarbitone

It induces rapid and smooth induction and recovery.
Its termination of effect is due to Re-distribution (It is lipid soluble. So, highly perfused organs like brain receive more concentration and then drug moves to periphery).
Give less dose of this drug.

Pentobarbitone

It is metabolized

Propofol

It induces smooth & rapid induction and recovery.
Its termination of effect is due to metabolism because drug moves to all body parts.

Chloral-Hydrate

It induces slow induction but prolonged recovery.
Termination is due to metabolism.
Hypnotic in nature due to metabolite called Trichloro Ethanol.
Perivascular leakage also leads to necrosis.
Still used in equines.
Pre-anesthetic agents are used with these drugs.

Anesthetic Agents & Anesthesia

2010-11-28T03:25:00.001-08:00

Anesthesia is the loss of sensation by giving anesthetic agents.
Agents which cause the loss of sensation are called as anesthetic agents.

These are of two types;

Local

These cause loss of sensation but animal is conscious.

General

These cause loss of sensation due to unconsciousness.

Objectives of Anesthesia

Sensory block to have analgesia. In this, sensory stimuli from the periphery are blocked.
Mental block to have hypnosis or Amnesia (animal know nothing, what is happening around). Activity of CNS is blocked.
Motor block to have muscle relaxation
Reflex block to have hyporeflexia
In case of local anesthetics, only one purpose is not the case of interest which is the mental block.

Stages of Anesthesia

Based on ether anesthesia, there are following stages of anesthesia;
Excitement stage (voluntary movements occur)
Delirium stage (involuntary movements occur)
Surgical Stage
Medullary paralysis

There are 3 stages of anesthesia;

Induction
Maintenance
Recovery

Ideal Properties of Anesthetic Agent

It should cause rapid & smooth induction and recovery.
It should be easy to maintain anesthesia (light or deep).
It should be non-toxic and safe to internal organs.
It should be non-irritant.
It should be non-inflammable and non-explosive.
Myocardial sensitization to epinephrine should be least.
It should be compatible with other drugs.
It should be easily available, cheap and easy to administer.

Pre-anesthetic Agents

These are the drugs given before anesthesia.

Why to give?

To reduce anxiety of patient
To reduce the amount of anesthetic agent
To reduce the adverse effects of anesthetic agent
To reduce the toxicity problems
To reduce secretions especially Bronchial & Salivary
To increase analgesia

Examples

Opiods (Morphine, Mepridine) which induce analgesia
Tranquilizers (Xylazine, Acepromazine) which reduce anxiety
Anticholinergic drugs (Atropine sulphate, scopolamine) which reduce secretions
Muscle relaxants (Gallamine, Pancuronium, d-tubocurarine, succinylcholine)

Medication during Anesthesia

To reduce Blood pressure
To induce muscle relaxation
To stop bleeding

Post-Anesthetic Medication

Analgesics
Anti-inflammatory
Anti-microbial
Cholinergic drugs to relieve retention of urine E.g. Bethanicol

Introduction to Pharmacology of CNS

2010-11-27T06:59:00.000-08:00

CNS consists of two main organs;

Brain
Spinal Cord
This is the information superhighway of the body. It carries information up to the brain and instructions back down.

Brain

It consists of following parts;

Cerebellum

Mostly deals with movement. It regulates and coordinates movement, posture and balance. Also involved in learning movement

Cerebrum

The cerebrum or cortex is the largest part of the human brain, associated with higher brain function such as thought and action.

Midbrain

Midbrain/ Mesencephalon- the rostral part of the brain stem, which includes the tectum and tegmentum
It is involved in functions such as vision, hearing, eyemovement, and body movement.

Types of Drugs in CNS

In CNS, synapses are the main junctions at the neuronal terminals.
Drugs are based on the type of neurotransmitters which are of 2 types;
Excitatory
Inhibitory

Stimulants

Drugs stimulating the excitatory neurotransmitters are called stimulants. E.g. Ach, Dopamine, epinephrine and nor-epinephrine.

Depressants

Drugs stimulating inhibitory neurotransmitters are called depressants. E.g. GABA (gamma amino butyric acid)(Brain), Glycine (spinal cord).
Depressants are mainly used in human practice.

Stages of Stimulation

Stages of Depression

Terminology

Sedation

There is slight depression but animal is awake.

Hypnosis

Animal is greatly depressed and seems to be asleep but can be awakened.

Tranquilizers

Slight Depression but animal behaves abnormally to external stimuli.

Narcosis

There is greater depression and animal is asleep and can be awakened but will again sleep. There is good analgesia.

Anesthesia

Animal is under greater depression and asleep but cannot be awakened. There is hyporeflexia.

Dissociative Anesthetics

Animal is superficially anesthetized and there is myotonia (movement in muscles).

There is analgesia but reflexes are present.

Basal Anesthetics

This anesthesia is maintained by other agents.

Adrenergic Blocking Agents...Pharmacology

2010-11-27T06:10:00.000-08:00

Adrenergic blocking agents are drugs that selectively inhibit specific receptor sites from sympathetic stimulation.
Blocking agents may interact with specific alpha and beta receptors. The release of nor-epinephrine from storage sites may be blocked.

Types of Adrenergic Blocking Agents

Adrenergic blocking agents are of two types;

α-Blockers
β-Blockers

α-Blockers

Phenoxybenzamine is the prototype drug which blocks α-1 and α-2 receptors.
Phentolamine, Tolezoline…… blocks α-1 and α-2 receptors
Przosine, Doxazosine, Terazosine….. Blocks α-1 receptors
Atipamazole…. blocks α-2 receptors

β-Blockers

Propranalol is the prototype drug which blocks both types of beta receptors.
Timolol, Ndolol, Pindolol also block the both types of beta receptors.
Atinilol, Esmalol blocks beta-1 receptors.
Butamoxine blocks beta-2 receptors.
Labetalol, Carvedalol block both alpha & beta receptors.

Therapeutic Uses

α-Blockers

Phenoxybenzamine blocks α-1 and α-2 receptors by making covalent bond, It is irreversible inhibition.
Other alpha blockers are reversible inhibitors.
For hypertension, these drugs are used.
Orthostatic Hypotension…In standing condition, hypotension occurs due to these drugs. So, initial dose should be given before bed.
Pheochromocytoma….Tumor of chromafin cells in adrenal glands, so, adrenaline quantity increased and Blood pressure remains constantly high. To diagnose it, phenoxybenze is used which will lower the blood pressure.
To remove the toxicity of α-2 agonists, alpha-2 antagonists are used.

β-Blockers

These are used as anti-hypertensive drugs. E.g. propranalol
Timolol is used to treat glaucoma by decreasing the intraocular pressure.

Adrenergic Drugs..Pharmacology

2010-11-27T04:56:00.000-08:00

Sympathomimetic drugs are substances that mimic the effects of the sympathetic nervous system, such as catecholamines, epinephrine (adrenaline), norepinephrine (noradrenaline), dopamine, etc. Such drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.
These drugs act at the postganglionic sympathetic terminal, by directly activating postsynaptic receptors, blocking breakdown and reuptake, or stimulating production and release of catecholamines.

There are two types of adrenergic drugs.

Direct Acting Drugs
Indirect Acting Drugs

Direct Acting Drugs

These are of two types

Natural compounds (catecholamines)

These include;

Epinephrine
Nor-epinephrine
Dopamine
If these catecholamines are released from nerve fibers, these are called neurotransmitters.
If released from glands, these are called as hormones.
If released from the outside, these are called as drugs.

Synthetic Compounds

These are of further two types;

α-agonists

These stimulate α receptors. These include;

Phenylephrine, Methoxyline (stimulate α-1 receptors)
Clonidine, Detomedine, Xylezene (stimulate α-2 receptors)

β-agonists

Isoprotalenol (stimulate β-1 & β-2 receptors)
Dobutamine (stimulate β-1 receptors)
Terbutalin, Sulbutamol, Clenbutarol (stimulate β-2 receptors)

Indirect Acting Drugs

These increase level of nor-epinephrine on receptors. These stop removal of nor-Epinephrine by stopping re uptake or by increasing the release of nor-epinephrine from the storage vesicles. These are divided into 3 categories;

Releasers

These enhance release of Nor-epinephrine from the endings. These include Tyramine, Amphetamine and Ephedrine (mixed).

Uptake Inhibitors

These drugs block and reverse the activity of nor-epinephrine transporter (NET). NET is a transport protein present on surface of some cells that clears adrenaline and nor-adrenaline from the extracellular space and into the cells, thus terminating the signaling effect.
These drugs include cocaine, Triphenylamine.

MAO Inhibitors (MAOI)

Adrenaline and nor-adrenaline are metabolized by the enzyme monoamine oxidase. These drugs inhibit the activity of this enzyme, thus producing sympathomimetic effects.
These drugs include Isocarboxazid, Phenelzine, Iproclozide, Procarbazine, Hydralazine and Phenoxypropazine.

Prototype Drug

Prototype drug in adrenergic drugs is;

Adrenaline b/c it stimulates all four types of receptors.
Nor-adrenaline cannot stimulate β-2 receptors.
Others stimulate only 1 or 2 receptors.

Therapeutic Uses

Asthma can be treated by β-2 agonists.
Cardiac arrest can be treated by β-1 agonists.
Retention of Urine
To decrease the intestinal motility
Vasoconstriction to increase blood flow and treat nasal congestion
Spray of α-1 agonist during surgery to decrease bleeding from small blood vessels
To enhance the duration of action of local anesthetics, adrenaline is used which decrease the absorption of anesthetic by causing vasoconstriction.
Cocaine is used as local anesthetic but vasoconstrictor is not used along with it b/c it is itself a vasoconstrictor.
Stimulate CNS E.g. Cocaine
Some used in allergic reactions
Some used to delay the labor condition of uterus near parturition to manage the delivery at proper time.
Glycogenolysis and gluconeogenesis are increased by stimulation of β-receptors in liver, muscles and adipose tissue.

Adrenergic Receptors..Pharmacology

2010-11-27T04:50:00.000-08:00

Two types of receptor sites are theorized to explain adrenergic effects.

Alpha-Receptors

Alpha-receptors are associated mainly with increased contractibility of vascular smooth muscle and intestinal relaxation.

Alpha1

The alpha1 is located at postsynaptic effector sites to stimulate transmitter release in smooth muscle. For example, the smooth muscle of peripheral blood vessels is contracted in alpha1 stimulation.

Alpha2

The alpha2 receptor site is located presynaptic on axon terminals to inhibit the release of nor-epinephrine (the transmitter). The effects of alpha2 stimulation results in relaxation of the intestinal tract--motility and tone are decreased.

Beta-Receptors

Beta-receptors are associated with vasodilation and relaxation of nonintestinal smooth muscle and cardiac stimulation.
Beta1 Stimulation of beta1 receptor sites results in cardiac stimulation and lipolysis.
Beta2 Stimulation of beta2 receptor sites causes bronchodilation, relaxation of blood vessels (usually in skeletal muscles), and muscle glycogenolysis.

Alpha Receptor Site: Important features of the site include in order of importance:

An anionic site - which binds the positive ammonium group.
One hydrogen bonding area
A flat area non-polar area for the aromatic ring.

Beta Receptor Site: Important features of the site include in order of importance - also see the graphic on the left:

An anionic site - shown as Asp anionic negative acid group which binds the positive ammonium group.
Two hydrogen bonding areas - shown as two Serine with alcohol (OH) groups hydrogen bonding to the phenol OH groups of the NE.
A flat area non-polar area for the aromatic ring.

Tissue	Receptor Subtype	Agonists	Antagonists
Heart	beta1	NE, EP, dobutamine, xamoterol	atenolol, metoprolol.
Adipose tissue	beta1, beta 3?
Vascular Smooth Muscle	beta 2	EP, salbutamol, terbutaline, salmeterol	butoxamine
Airway Smooth Muscle	beta 2	terbutaline, salbutamol, salmeterol and zinterol,	butoxamine
Smooth muscle contraction	alpha 1	NE, EP, phenylephrine, oxymetazoline)	prazosin, doxazocin
Inhibition of transmitter release Hypotension, anaesthesia, Vasoconstriction	alpha 2	clenbuterol, alpha-methylnoradrenaline, dexmedetomidine, and mivazerol, clonidine, clenbuterol	yohimbine, idazoxan, atipamezole, efaroxan, and rauwolscine

Receptor Sites
alpha-receptor	beta-receptor
Vasoconstriction	vasodilation (b2)
iris dilation	cardioacceleration (b1)
intestinal relaxation	intestinal relaxation (b2)
intestinal sphincter contraction	uterus relaxation(b2)
bladder sphincter contraction	bronchodilation (b2)

Family Oestridae..Genus Oestrus (Nasal Bot Flies)

2010-11-26T05:51:00.000-08:00

Larvae of these flies spend most of their time in the nasal passage of sheep & Goat. So called nasal bots
Adult flies are having short life span (1 week) whereas larvae having 1 year or more of life span.

Morphology

Adult flies are 1cm in size and of grey color.
Small dark spots are present on the abdomen with a covering of short brown hair.
Size of Larvae is 3cm and color is yellowish white. Larva is tapering anteriorly with prominent step posteriorly.
Body is segmented having dark transverse bands dorsally (each segment).

Nasal Bot fly injecting larvae

Life Cycle

Adult female is viviparous and produce larvae.
Sheep become infected by squirting of jet of liquid containing larvae.
During the flight, fly deliver 25 larvae.
Newly emerged larva is 1mm in length.
Larva migrates from nasal passage to frontal sinuses.
Larva feed on mucous secreted by movement of larva.
In the nasal passage, larva mould to L2.
In the frontal sinuses, larva completes their development and then migrates to nostrils where they are active throughout the year.
Become dormant in winter season if temperature is below 18.
From the nostrils, L3 larvae fall on the ground and from larva, pupa develops.
From the pupa, adult emerges. Adult having very short life span
Survive for only 1 week and during this period, produce about 500 larvae.

Pathogenic effects

Itching and Irritation
Rubbing the nostrils against hard objects
Nasal discharge which later on becomes mucopurulent
In coordination, convulsions
Also called false gid (signs resembling coenurus cerebralis)
Cause swelling of eyes in human called as keratoconjunctivitis and inflammation of lips called stomatitis
Loss of weight

Treatment

Refoxanide, Ranide…. 1ml/25kg BW subcutaneously
Nitroxynil, Trodex….1ml/20kg BW subcutaneously
Ivermectin………….1ml/50kg BW subcutaneously

Control

Regular use of insecticidal drugs should be followed.

Family Oestridae..Genus Hypoderma (Warble Flies)

2010-11-26T05:44:00.000-08:00

These are hairy flies.

Adult flies having primitive and non-functional mouth parts.

Adult life span is short.

Larva having functional mouth parts and long life span

There are 3 important generas;

Hypoderma
Oestrus
Gaterophilus

Genus Hypoderma

Also called warble flies
Cause great economic losses
Affect cattle, buffalo, sheep, goat, equines and sometimes human beings.
These flies are present mainly in lower Punjab areas.
Species include;
H. Bovis
H. Liniatum

Morphology

These flies resemble honey bees.
Have one pair of wings, Yellow orange abdomen having yellow orange hair with a broad band of black hair in middle.
Larva size is 2.5-3cm and color is dirty white when emerges but becomes dark brown later on.
Larva is barrel shaped and segmented body. Each segment bears spines.
Larva is tapering interiorly and color of pupa is black.

Life cycle

Adult flies are active during warm month of the year and lay eggs.
Egg attaches to the lower region of the leg having hairs. H.Bovis has single eggs but H.Liniatum eggs are in a row of 6. Eggs of H.Bovis are above hock region and that of H.Liniatum are below hock region.
Egg hatch and larva develop (L1). Size of L1 larva is 1mm. L1 crawl down the Hair, Penetrate Hair follicles and reaches the Diaphragm region. This migration is aided by paired mouth hooks and secretion of proteolytic enzymes.
From the diaphragm, L1 move toward resting site during autumn. Resting site of H.Bovis is epidural fat of spinal canal and that of H.Liniatum is sub mucosa of esophagus.
They spend winter over there.
With the onset of spring season, L1 mould to L2 and become active and move toward skin of back.
With the onset of summer season, L2 mould to L3. L3 can be seen under the skin. These come out of the skin and fall on the ground. They move in the soil for some time.
From the larva, pupa and from the pupa, adult emerges.
Adult copulate, female lay eggs and then die within 1-2 weeks.

Pathogenic Effects

Creates disturbance and cause restlessness for the animals and human beings due to buzzing noise
Greenish yellow gelatinous mass is formed on the damaged skin of back and it is called as Butcher Jelly.
Due to buzzing noise, meat production is reduced and also milk production.

Treatment & Control

Ivermectin…. Ivotec, Ivomec (1ml/50kg B.W subcutaneously)
Use insecticides;
Organo Chlorine…… DDT, hexachlorocyclohexane/ benzene hexachloride
Organic phosphate…. Trichlorofen, neguvan, cumafex, neocidal, diazinon and asuntal
Synthetic pyrethroid...Cypermethrine and Ecoflee
Carbamates…
To treat toxicity, Atropine sulphate is used.

Family Muscidae..Genus Glossina (TseTse Flies)

2010-11-26T05:32:00.000-08:00

Also called TseTse flies
Some classify it in family muscidae and some in Glossinidae family.
It is found in Africa on more than 10 million kilometer area.
It is important vector of many Human & Animal diseases.

Morphology

Adult flies are long, narrow and yellow to dark brown in color.
Size is 6-15mm and mouth is projecting forward.
Wings held over the abdomen like a pair of close scissors when at rest.
Mouth parts are composed of U-shaped Labium with rasp labella which lie at the terminal region of Labium and upper sharp labrum.
B/W Labium and Labrum, Hypopharynx is present which carries salivary duct and delivers anticoagulant to Host tissue.
In the center of the wings, there lies hatchet or cleaver.

Life Cycle

Female is viviparous and produce 8-12 larvae in its life time.
Maturation of larva takes place in 10 days.
Size of larva is 8-10mm.
Color of larva is creamy white and segmented body and ear shaped Protuberance which is used for respiration.
From the larva, pupa develops. Pupa stage is 4-5 weeks. Pupa is barrel shaped and Dark brown in color.
From the pupa, adult emerges. Adult requires several blood meals for a period of 16-20 days before ovary matures and egg laying starts.

Pathogenic Effects

Create great restlessness for animal and human beings.
It causes production losses.
These flies are important vectors of Trypanosomiasis (human & animals).

Treatment & Control

Use insecticides;
Organo Chlorine…… DDT, hexachlorocyclohexane/ benzene hexachloride
Organic phosphate…. Trichlorofen, neguvan, cumafex, neocidal, diazinon and asuntal
Synthetic pyrethroid...Cypermethrine and Ecoflee
Carbamates…
Destroy the bushes.
Killing of the game animals which act as reservoir of infection because these animals provide blood to flies is necessary.
Trap the flies with black cloth and kill them. It is the best method.

Associations..Epidemiology

2010-11-24T05:22:00.001-08:00

Variables

A variable is any observable event that can vary;

Examples:

Weight
Age of an animal
Number of cases of disease

Study variable

A study variable is any variable that is being considered in an investigation

Response and explanatory variables

A response variable is one that is affected by another (explanatory) variable

Example:

Effects of dry cat food on the occurrence of urolithiasis, cat food is the explanatory variable and urolithiasis is the response variable

Types of association

Association is the degree of dependence or independence between two variables.

Main types of association

Non-statistical association
Statistical association

Causal network

Non-statistical association

A non-statistical association between a disease and a hypothesized causal factor is an association that arises by chance
Frequency of joint occurrence of the disease and factor is no greater than would be expected by chance

Example

Mycoplasma felis has been isolated from the eyes of some cats with conjunctivitis.
This represents an association between the Mycoplasma and conjunctivitis in these cats
Surveys have shown that M. felis also can be recovered from the conjunctivae of 80% of apparently normal

Analysis:

Association between conjunctivitis and the presence of M. felis arose by chance

Statistical association

Variables are positively statistically associated when they occur together more frequently than would be expected by chance
Negatively statistically associated when they occur together less frequently than would be expected by chance

Path diagrams

Indicating the paradigm
An example of causal and non-causal statistical associations
A = Cause of disease (explanatory variable); B and C = manifestations of disease
(Response variables) causal association; non-causal association

Infection of cattle with Haemonchus contortus

If infection of cattle with Haemonchus contortus were being investigated, then the following positive statistical associations could be found:

Between the presence of the parasite and Abomasal mucosal hyperplasia;
Between the presence of the parasite and anaemia;
Between Abomasal mucosal hyperplasia and anemia

The first two associations are causal and the third non-causal

Abomasal mucosal hyperplasia and infection with H. contortus are risk factors for anemia, that is, their presence increases the risk of anemia

Confounding

Confounding (Latin: confundere = to mix together) is the effect of an extraneous variable that can wholly or partly account for an apparent association between variables

Confounder

A variable that confounds is called a confounding variable or confounder
A confounding variable is distributed non-randomly (i.e., positively or negatively correlated with the explanatory and response variables that are being studied)
A confounding variable generally must:
Be a risk factor for the disease that is being studied;
Be associated with the explanatory variable, but not be a consequence of exposure to it.

The association between coffee drinking and pancreatic cancer

Schematic representation of the issue of potential confounding

Causal models

The associations and interactions between direct and indirect causes can be viewed in two ways, producing two causal 'models.

Causal model 1

The relationship of causes to their effects allows classification of causes into two types:

Sufficient

Necessary

Sufficient cause

A cause is sufficient if it inevitably produces an effect (assuming that nothing happens that interrupts the development of the effect, such as death or prophylaxis).
A sufficient cause virtually always comprises a range of component causes; disease therefore is multifactorial.

Example

Distemper virus-cause of distemper, although the sufficient cause actually involves

Exposure to the virus
Lack of immunity
Other components

It is not necessary to identify all components of a sufficient cause to prevent disease because removal of one component may render the cause insufficient

Necessary cause

If a cause is a component of every sufficient cause, then it is necessary

A necessary cause must always be present to produce an effect

Example

Cause that is necessary but not sufficient is infection with Actinobacillus ligneresi, which must occur before actinobacillosis ('wooden tongue') can develop

Component causes therefore include factors that have been classified as

Predisposing factors:

Which increase the level of susceptibility in the host (e.g., age and immune status?)

Enabling factors:

Which facilitate manifestation of a disease (e.g., housing and nutrition?)

Precipitating factors:

Which are associated with the definitive onset of disease (e.g., many toxic and infectious agents)

Reinforcing factors:

Which tend to aggravate the presence of a disease (e.g., repeated exposure to an infectious agent in the absence of an immune response).

Example

Pneumonia is a disease that has sufficient causes, none of which has a necessary component.
Pneumonia may have been produced in one case by heat stress where a dry, dusty environment allowed microscopic particulate matter to reach the alveoli.
Cold stress could produce a clinically similar result

Formulating a causal hypothesis

First step in any epidemiological investigation of cause is descriptive.

A description of time, place, and population is useful initially.

Time

Associations with year, season, month, day, or even hour in the case of food poisoning investigations, should be considered.
Information on climatic influences, incubation periods and sources of infection

Example

An outbreak of Salmonellosis in a group of cattle may be associated with the introduction of infected cattle feed

Place

The geographical distribution of a disease may indicate an association with local geological, management or ecological factors
Epidemiological maps are a valuable aid to identifying geographical associations

Population

The type of animal that is affected often is of considerable importance.
Hereford cattle are more susceptible to squamous cell carcinoma of the eye than other breeds, suggesting that the cause may be partly genetic
An epidemiological investigation is similar to any detective novel that unfolds a list of 'suspects' (possible causal factors), some of which may be non-statistically associated with a disease, and some statistically associated with the disease, either causally or non-causally.

Principles for establishing cause: Hill's criteria

The British medical statistician, Austin Bradford Hill, proposed several criteria for establishing a causal association including

The time sequence of the events
The strength of the association
Biological gradient
Consistency
Compatibility with existing knowledge

Time sequence

Cause must precede effect
Unless bacterial infections were present before the mares became infertile (incorrect to infer the bacterial infections)

Strength of association

If a factor is causal, then there will be a strong positive statistical association between the factor and the disease.

Biological gradient

If a dose-response relationship can be found between a factor and a disease, the plausibility of a factor being causal is increased.
This is the basis of reasoning by the method of concomitant variation

Examples

Frequency of milking in relation to Leptospirosis
Smoking in relation to lung cancer

Consistency

If an association exists in a number of different circumstances, then a causal relationship is probable.
This is the basis of reasoning by the method of agreement.

An example is bovine hyperkeratosis

The disease was called 'X disease' because initially the cause was unknown. It occurred in different circumstances:

In cattle that were fed sliced bread;
In calves that had been licking lubricating oil;
In cattle that were in contact with wood preservative.

The bread slicing machine was lubricated with similar oil to that which had been licked by the calves. The lubricating oil and the wood preservative both contained chlorinated naphthalene. This chemical was common to the different circumstances and subsequently was shown to cause hyperkeratosis

Compatibility with existing knowledge

It is more reasonable to infer that a factor causes a disease if a plausible biological mechanism has been identified than if such a mechanism is not known

Example

Smoking can be suggested as a likely cause of lung cancer because other chemical and environmental pollutants are known to have a carcinogenic effect on laboratory animals

Adrenergic Transmission..Pharmacology

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Synthesis

Tyrosine is actively transported inside the presynaptic membrane.
Inside nerve fibers, tyrosine is converted into DOPA (dihyroxy phenyl alanine) by tyrosine hydroxylase. This is the rate limiting step.
DOPA is converted into dopamine by decarboxylase enzyme.

Storage

Dopamine is shifted inside storage vesicles. Here, it is converted into Nor-Epinephrine by Dopamine β hydroxylase. This enzyme is present in storage vesicles.
Outside vesicles, MAO (mono amine oxidase) metabolizes dopamine.
Nor-Epinephrine is converted into Epinephrine by N-Methyl Transferase.

Release

Nor-epinephrine is released by fusion of vesicles with presynaptic membrane facilitated by calcium.
Nor-epinephrine is released into cleft, Calcium channels open and calcium enters inside presynaptic membrane. This calcium causes fusion of vesicles with membrane.

Binding

Nor-epinephrine binds with alpha or beta receptors. Both of these are of two types;

RECEPTOR SITE THEORY OF ADRENERGIC TRANSMISSION

Two types of receptor sites are theorized to explain adrenergic effects.

Alpha-Receptors

Alpha-receptors are associated mainly with increased contractibility of vascular smooth muscle and intestinal relaxation.

Alpha1

The alpha1 is located at postsynaptic effector sites to stimulate transmitter release in smooth muscle. For example, the smooth muscle of peripheral blood vessels is contracted in alpha1 stimulation.

Alpha2

The alpha2 receptor site is located presynaptic on axon terminals to inhibit the release of norepinephrine (the transmitter). The effects of alpha2 stimulation results in relaxation of the intestinal tract--motility and tone are decreased.

Beta-Receptors

Beta-receptors are associated with vasodilation and relaxation of nonintestinal smooth muscle and cardiac stimulation.

Beta1

Stimulation of beta1 receptor sites results in cardiac stimulation and lipolysis.

Beta2

Stimulation of beta2 receptor sites causes bronchodilation, relaxation of blood vessels (usually in skeletal muscles), and muscle glycogenolysis.

Removal

Uptake-1

Nor-epinephrine is actively uptaken into presynaptic membrane.

Uptake-2

Some nor-epinephrine enters into effector cells and metabolized by MAO.

Anticholinergic Drugs..Pharmacology

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An anticholinergic agent is a substance which blocks the neurotransmitter Acetylcholine in the CNS and PNS. Classic example is Atropine.
Atropine is specific antagonist for muscarinic receptors. It is competitive inhibitor.
Atropine is selective for nicotinic and muscarinic receptors.
Anticholinergics are administered to reduce the effects mediated by acetylcholine on acetylcholine receptors in neurons through competitive inhibition. Therefore, their effects are reversible.
A parasympatholytic element, also referred to as anticholinergics, reduces the activity of the parasympathetic nervous system.
The term parasympatholytic typically refers to the effect of a drug, although some poisons, such as organophosphates act to block the parasympathetic nervous system as well.

Parasympathetic Nervous System

75% of all parasympathetic nerve fibers are in the vagus nerves
These nerves supply the thoracic and abdominal organs, which innervate the heart, lungs, esophagus, stomach, and small intestine, proximal half of the colon, liver, gallbladder, pancreas and upper portions of the ureters
Also supply the muscles of the eyes, lacrimal, nasal, submaxillary, and parotid glands; descending colon and rectum; lower portions of the ureters, bladder and genitalia
All are regulated by acetylcholine—exerts excitatory effects at nerve synapses and neuromuscular junctions; and inhibitory effects at peripheral sites e.g. heart

Classification of Anticholinergics

Anticholinergics are classified according to the receptors that are affected:
Antimuscarinic agents operate on the muscarinic acetylcholine receptors. The majority of anticholinergic drugs are antimuscarinics.
Antinicotinic agents operate on the nicotinic acetylcholine receptors. The majority of these are non-depolarising skeletal muscle relaxants for surgical use, along with a few of the depolarising agents and drugs of other categories structurally related to curare. These include Ganglionic blocking agents and neuromuscular blocking agents.

Antimuscarinic Agents
Classification
Natural Alkaloids

Atropine
Hyoscine (scopolamine)
Extract of Belladona

Semisynthetic

Homatropine
Encatropine
Methylatropine
Methscopoline

Synthetic

Tropicamide
Glycopyrrolate
Pirenzeline

Mechanism of Action

Most anticholinergic drugs interact with the muscarinic receptors in the brain, secretory glands, heart, and smooth muscle
A few can also affect the nicotinic receptors. Glycopyrrolate (Robinul) is an example
Act by occupying receptor sites at parasympathetic nerve endings, thereby leaving fewer receptor sites free to respond to acetylcholine
Distribution of receptors is broad so effects of anticholinergics will be diffuse.

Effects

Effects on CNS

Scopolamine has greater effects on the CNS than atropine due to its ability to cross the blood-brain barrier.
Atropine and scopolamine cause CNS depression characterized by amnesia, fatigue and reduction in rapid eye movement sleep.
Hyoscine has anti-emetic activity, so is used for motion sickness.

Effects on Heart

Atropine acts on the M2 receptors of the heart and antagonizes the activity of acetylcholine. It causes tachycardia by blocking vagal effects on the sinoatrial node.
If atropine is given by intramuscular or subcutaneous, it causes initial bradycardia.
Decreased cardiovascular response to vagal stimulation resulting in tachycardia
Increases vagal tone Ex. Atropine.

Effects on Body tissues

Bronchodilation and decreased respiratory tract secretions.
Antispasmotics of GI tract due to decreased tone and motility
Mydriasis and cyclopegia Normally do not increase IOP but caution as can precipitate acute glaucoma.
Can cause decreased oral secretions, decreased sweating, and relaxation of urinary bladder
Ataxia; loss of coordination
Decreased mucus production in the nose and throat; consequent dry, sore throat
Xerostomia or dry-mouth with possible acceleration of dental caries
Cessation of perspiration; consequent decreased epidermal thermal dissipation leading to warm, blotchy, or red skin
Increased body temperature
Pupil dilation (mydriasis); consequent sensitivity to bright light (photophobia)
Loss of accommodation (loss of focusing ability, blurred vision — cycloplegia)
Double-vision (diplopia)
Increased heart rate (tachycardia)
Tendency to be easily startled
Urinary retention
Diminished bowel movement, sometimes ileus - (decreases motility via the vagus nerve)
Increased intraocular pressure; dangerous for people with narrow-angle glaucoma
Shaking

Therapeutic Uses

Uses include GI, GU, ophthalmic and respiratory disorders, bradycardia and in Parkinson’s disease.
Used preoperatively (preanesthetics)

Use in GI Disorders

Helpful in treating irritable colon or colitis
Useful in gastritis, pylorospasm and ulcerative colitis as they slow motility

Use in GU (Genitourinary) disorders

Antispasmotic effects seen in overactive bladder and in urinary incontinence

Urinary Antispasmotics

Flavoxate (Urispas)—relieves dysuria, urgency, frequency, and pain with GU infections
Oxybutynin (Ditropan) has direct antispasmodic effects on smooth muscle and anticholinergic effects. Decreases frequency of voiding
Tolterodine (Detrol) is competitive, antimuscuranic anticholinergic that inhibits contraction. More selective for this area than elsewhere in the body

Ophthalmology

Mydriatic and cycloplegia for examinations and surgery

Respiratory

In bronchospasm whether related to asthma or COPD
Atrovent very useful for its bronchodilating effects

Cardiology

Atropine is used to increase heart rate in symptomatic bradycardias and higher blocks

Parkinson’s disease

Useful in those with minimal side effects
Those who cannot take Levodopa
Helpful in decreasing salivation, spasticity and tremors

Preoperational

Help prevent vagal stimulation and potential bradycardia
Reduce respiratory secretions as well

Antinicotinic Agents

These include;

Ganglionic Blocking Agents
Neuromuscular Blocking Agents

Ganglionic Blocking Agents

These are the drugs which inhibit postganglionic transmission by acting as nicotinic antagonists.

These include;

Hexamethonium
Pentamethonium
Trimethophan
Mecamylamine

Mechanism of Action

The Ganglionic blocking agents are drugs which act by competiting with Acetyl choline (Ach) from the cholinergic receptors present in the autonomic post ganglionic neurons.
Since the ganglia of both the sympathetic and parasympathetic nervous systems are cholinergic, these drugs interrupt the outflow through both systems.
They are used mostly for their interruption of the sympathetic outflow in hypertension, vasopastic disorders and peripheral vascular disease. Thus lowering the B.P and increasing the peripheral blood flow.

Based on the mechanism these are classified as follows.

By Interfering with Ach release - Triethyl choline, Hemicholinium
By interference with post synoptic action of Ach - Eg: Hexamethonium
By prolonged depolarization - E.g.: Nicotine

Effects

Therapeutic Uses

Trimethaphan is used in case of Increased Blood Pressure (Antihypertensive).
Mecamylamine is also hypertensive.
Ganglionic blockers are used less frequently now than they were in the past, because more selective agents are now available. However, they are still used in some emergency situations, such as aortic dissection.

Side Effects

Cardiovascular: Orthostatic (postural) hypotension, Tachycardia
GIT: Dry-mouth, GIT atony, urine retention, digestive problems
Sexual Dysfunction: Failure of erection and ejaculation

Neuromuscular Blocking Agents

Neuromuscular blocking drugs block neuromuscular transmission at the neuromuscular junction causing paralysis of the affected skeletal muscles.

These are of two types;

Competitive Antagonists (Non-depolarizers) - These include;

D-tubocurarine (prototype drug) is obtained from curare plant. It is also called aerohead poison.
Gallamine
Vecuronium
Pancuronium
Atracurium

Depolarizers

Suxamethonium (succinyl choline)
Decamethonium
Suxamethonium can be metabolized like acetylchline. So, duration of activity is short. It is metabolized by psuedocholinesterase/butyrylcholinesterase present in plasma.
Non-ruminants having high concentration of enzyme so shorter duration
Ruminants having low enzyme so longer duration

Mechanism of Action

Neuromuscular blocking agents can block the neuromuscular transmission by
Inhibiting acetyl choline synthesis
Inhibiting Ach release and inhibit calcium entry have neuromuscular block.
Interfering with the post synoptic action of Ach
Non depolarizing blocking agents act by competitive antagonism at Ach receptos of the end plate and these largely accounts for their action.
Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.

Differences b/w depolarizers and non-depolarizers

Therapeutic Uses

Preoperational
Fracture cases
Antihypertensive
To restrain vicious animals
As preanesthetic during passing of tracheal tube

Individual Anticholinergic Drugs

Atropine—prototype

Antidote
Belladonna alkaloid

Ipratropium (Atrovent).

Useful in rhinorrhea
Also excellent bronchodilator

Scopolamine, similar to atropine

Depresses CNS and causes amnesia, drowsiness, euphoria, relaxation and sleep.
Also good for motion sickness
Given parenterally, orally and transdermally.

Centrally Acting Anticholinergics

Benztropine (Cogentin)

Temporary use in Parkinson’s disease
Useful for dystonic reactions caused by antipsychotics

Trihexyphenidyl (Trihexy)

Also used for txing EPS by some antipsychotics.
Contraindicated in glaucoma

Toxicity Effects

Anticholinergic overdose syndrome is characterized by: Hyperthermia, delirium, dry mouth, tacycardia, ileus, and urinary retention. Seizures, coma and respiratory arrest may occur.
TX—activated charcoal, Antilirium, cooling agents (ice bags, cooling blankets, tepid baths).

Family Muscidae..Genus Stomoxy (Stable Flies)

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Also called as stable flies
These are biting house flies. Bite of the fly is very painful.
These are important vectors of many helminthes and protozoan infections.
Specie important is S. Calcitran.

Morphology

Size if 5.5-7.5mm and color of the fly is grey.
Four dark, longitudinal stripes are present on the thorax.
Mouth (proboscis) is projected forward.
Mouth part is composed of labium, labrum and hypopharynx which carries salivary duct and delivers anticoagulant into host tissue.

Life Cycle

Adult female lay eggs on decaying organic matter or rotting material or wheat straw, rice straw and hay contaminated by urine and feces of animals.
Eggs are laid in batches. Each batch contains 25-50 eggs.
Egg hatch in 1-4 days depending upon the environmental conditions.
From the egg, larva develops. Larva maturation takes place in 6-30 days depending upon the environmental conditions. 27-29°C is the optimum temperature for larval development.
From the larva, pupa emerges.
From the pupa, adult emerges.
It requires 12-60 days for completion of life cycle (egg-adult).
Adult requires several blood meals before ovary matures and egg laying starts.

Pathogenic Effects

Mouth parts swing downward and penetration of skin is achieved by rasping effect of teeth which lies at the end of the labium.
It is very painful bite for animal.
3 minutes are required for a complete blood meal.
Feeding is often interrupted thus allowing pathogenic organisms to enter into the body of flies and multiply there.
Same fly when sucking blood from another animal, transmits the pathogenic organism into the other animal.
Habronema (nematodal infection) and Trypnosomiasis (protozoan infection) are transmitted by these flies.
Creates restlessness for the animal and human beings
It causes production losses of 20-25 %.
Prefer strong sunlight to live and present in abundance on building and farm.

Treatment & Control

Provide good hygienic conditions.
Destruction of breeding places is very much important.
Proper drainage of the area is very important.
Use insecticides;

Organo Chlorine…… DDT, hexachlorocyclohexane/ benzene hexachloride

Organic phosphate…. Trichlorofen, neguvan, cumafex, neocidal, diazinon and asuntal

Synthetic pyrethroid...Cypermethrine and Ecoflee

Carbamates…

Use of flies repellant sprays such as spoton and sporon.
Valuable animals must have ear tags, nose ring and tail bands impregnated with insecticides.
Lower the animal movement during maximum activity of flies.

Cohort Study..Epidemiology

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Cohort is a group of individuals having some common characteristics. These characteristics may be birth date, age, marriage date or smoking.
Cohort study is called as prospective study which means “looking forward”.
You know the risk and disease comes later.
It is also called incidence study because healthy individuals become diseased after few years and become a new case.

Indications

Cohort study is conducted only when you have evidence about the exposure and disease.
When exposure is rare but incidence is higher in exposed e.g. exposure to uranium is rare but if exposed, cancer chances are very higher.
When sufficient funds are available, cohort study is conducted.
When follow up is easy or possible, cohort study is conducted. I.e. completion of study is necessary (at least for 25 years).
It starts with people free of disease.
Exposure Status is known at baseline.
Outcome occurs after follow up.

Components:

Cohort
Exposure status

Considerations while selecting Group

Exposed and non-exposed groups should be free of disease.
Both groups should be comparable.
Both groups should be equally susceptible.
Diagnostic criteria for disease

Elements of Cohort Study

Selection

Selection of study i.e. subjects

Obtaining data

Obtaining data from study subjects (obtain exposure status through interview, questionnaire and through mails). Medical tests should be performed to check some disease in these subjects.

Comparison group

Comparison group is selected.
Non-exposed group is your comparison group. It is called as internal comparison. It is difficult.
External comparison is easy because you already know that who are smokers and who are non-smokers. Non-smokers are your comparison group.
Compare with general population. We will take two groups. E.g. cancer in uranium miners and cancer in general population. In this, uranium miners are study group and general population is comparison group.

Follow up

You will follow the exposed and non-exposed for a particular period depending upon the period of the development of the disease. e.g. 10, 20, 25 years
Drawbacks of follow up include death of investigator, deaths from study group, loss of follow up or non-availability of funds.

Analyses

Two factors are calculated;

Incidence Rate (IR)
Relative Risk (RR)

Causality..Epidemiology

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Philosophical background

Causation

Deals with the relationship between cause and effect

The Classical period

Aristotle-doctrine of four causes

Material cause

What 'stuff' (matter) a thing comprises-some combination of the four elements:
Earth
Air
Fire
Water

Formal cause

The 'form and pattern' of a thing, or those properties without which a thing would not exist as it does

Efficient cause

Which is the maker of a thing (and by which the formal cause is therefore explained)

Final cause

Which is the purpose of the thing (and therefore, in the case of natural things, usually synonymous with the formal cause)

The Scholastics

Christian mediaeval philosophers (termed the 'Scholastics') generally endorsed Aristotle's ideas, but focused on God as the efficient cause of all things
Individuals were secondary efficient causes of things
God as the primary cause was a subject of debate during this period.

The 'Modern' period

Explain events mathematically in terms of

‘How' (description)
‘Why' (explanation)

Causal inference

Scientific conclusions are derived by two methods of reasoning:

Deduction
Induction

Deduction

Deduction is arguing from the general to the particular; that is, a general case is established, from which all dependent events are argued to be true
Example: Thus, if one posits the truth of the general proposition 'all dogs are mammals', it follows by deduction that any particular example of a dog will be a mammal

Induction

Arguing from the particular to the general
Example: A dog may be vaccinated against distemper virus, and shown to be immune to challenge with the agent, from which the conclusion is drawn that the vaccine prevents distemper in all dogs.

Why to identify cause?

Epidemiological studies are undertaken to identify causes of disease so that preventive measures can be developed and implemented, and their subsequent effectiveness identified
Investigations of cause are usually based on inductive reasoning

Methods of acceptance of hypotheses

Accept (or reject) a causal hypothesis by four methods

Tenacity-disregards opinion of others
Authority
Intuition
Scientific inquiry

Koch's postulates

Koch in the late 19th century formulated postulates about cause of infectious disease

These postulates state that an organism is causal if:

It is present in all cases of the disease
It does not occur in another disease as a fortuitous and non-pathogenic parasite
It is isolated in pure culture from an animal, is repeatedly passaged, and induces the same disease in other animals.

Koch's postulates brought a necessary degree of order and discipline to the study of infectious disease

Evans' rules

Alfred Evans (1976) has produced a set of rules that are consistent with modern concepts of causality:

The proportion of individuals with the disease should be significantly higher in those exposed to the supposed cause than in those who are not
Exposure to the supposed cause should be present more commonly in those exposed to the supposed cause than those without the disease, when all other risk factors are held constant
The number of new cases of disease should be significantly higher in those exposed to the supposed cause than in those not so exposed
Temporally, the disease should follow exposure to the supposed cause with a distribution of incubation periods on a bell-shaped curve
A spectrum of host responses, from mild to severe, should follow exposure to the supposed cause along a logical biological gradient
A measurable host response (e.g., antibody, cancer cells) should appear regularly following exposure to the supposed cause in those lacking this response before exposure, or should increase in magnitude if present before exposure; this pattern should not occur in individuals not so exposed
Experimental reproduction of the disease should occur with greater frequency in animals or man appropriately exposed to the supposed cause than in those not so exposed
Elimination (e.g., removal of a specific infectious agent) or modification (e.g., alteration of a deficient diet) of the supposed cause should decrease the frequency of occurrence of the disease
Prevention or modification of the host's response (e.g., by immunization or use of specific lymphocyte transfer factor in cancer) should decrease or eliminate the disease that normally occurs on exposure to the supposed cause

Variables

A variable is any observable event that can vary:

Examples:

Weight
Age of an animal
Number of cases of disease

All relationships and associations should be biologically and epidemiologically credible

Total Leukocyte Count

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Specimens

Double oxalated or EDTA blood
Capillary blood (specimen need not be a fasting sample).

Requirements

Microscope

Improved Neubauer Chamber

WBC pipette

WBC diluting fluid: It is prepared as follows:

Glacial acetic acid: 2.0 ml
1 % (w/v) gentian violet: 1.0 ml
Distilled water: 97 ml

This solution is stable at room temperature (25°C ± 5°C). A pinch of thymol maybe added as preservative.

Principle

The glacial acetic acid lyses the red cells while the gentian violet slightly stains the nuclei of the leukocytes.
The blood specimen is diluted 1:20 in a WBC pipette with the diluting fluid and the cells are counted under low power of the micro scope by using a counting chamber.
The numbers of cells in undiluted blood are reported per cu mm (μl) of whole blood.

Procedure

Draw blood up to 0.5 mark of a WBC pipette.
Carefully, wipe excess blood outside the pipette by using cotton. Draw diluting fluid up to 11 marks.
Mix the contents in the pipette and after five minutes by discarding few drops, fill the counting chamber and allow the cells to settle for two to three minutes.
Since Bulb pipettes are not recommended following procedure is performed
Make a 1:20 dilution of blood by adding 20 μl of blood to (1 38 ml of diluting fluid in a glass tube (10 * 75 mm) Cork the tube tightly and mix the suspension by rotating in a cell-suspension mixer for at least 1 minute. Fill the Neubauer counting chamber by means of a Pasteur pipette or glass capillary.
Focus on one of the ‘W’ marked areas (each having 16 small squares) by turning objective to low power. (10 X).
Count cells in all four W marked corners.

Calculations

Number of white cells/cu mm (μl) of whole blood = (number of white cells counted * dilution) / (area counted * depth of fluid)

Where:

Dilution = 20
Area counted 4 * 1 sq.mm = 4 sq.mm
Depth of fluid = 0.1 mm (constant)

Hence number of white cells per cu mm (μl) of whole blood = (No. of cells counted * 20) / (4 * 0.1) = No of cells counted * 50

No. of leukocyte per liter of blood = No. of cells per cu mm (ml) * 106 or

Use the following formula

WBC count / liter = [No. of cells counted (per 1mm2 area) / volume counted (μl)] * dilution * 106

Precautions taken are exactly the same as for REC counting technique.

The sources of error are also same as for RBC counting technique. However; in the case of WBC counting extra care is taken during the preparation and storage of WBC diluting fluid.
It should be perfectly free from dust particles and yeast cells, otherwise falsely high counts are obtained due to the presence of yeast cells and dust particles.

Normal values

Adults: 4,000-10,000/cu mm (μl)
At birth: 10,000-25,000/cu mm (μl)
1 to 3 years: 6,000-18,000/cu mm (μl)
4 to 7 years: 6,000-15,000/cu mm (μl)
8 to 12 years: 4,500-13,500/cu mm (μl)

Error of the total white cell count

The inherent distribution error = λ1/2, here λ = total number of cells in each area.
The error as high as 20% may make difference between 5.0 and 6.0 x 109 cells per liter, which is of little practical significance.
The error can be reduced by counting more cells. If 400 cells are counted the error is reduced to 5%.
Error may also be caused due to dirt clumped RBC debris or due to clumping of leukocytes.

Interpretation of Results:

Clinical Significance

Increase in total leukocyte count of more than 10,000/cu mm (μl) is known as

leukocytosis and decrease of less than 4 000 cu mm (μl) as leukopenia.

Causes of leukocytosis

Pathological

It is common for a transient period in infections. The degree of rise in leukocytes depends on the type and severity of the infection and the response of the body.
The infection may be 1) bacterial 2) viral 3) protozoal (malaria) or 4) parasitic (filaria, hookworm infection).
Leukocytosis is also observed in severe hemorrhage and in Leukemia.

Physiological

Age: At birth the total leukocyte count is about 18,000/cu mm (μl). It drops gradually to adult level.
Pregnancy: At ‘full term’ the total count tends to be about 12,000 to 15,000/cu mm (μl). It rises soon after delivery and then gradually returns to normal.
High temperature
Severe pain
Muscular exercise

Causes of Leukopenia

Certain viral and bacterial infections (typhoid) lead to leukopenia rather than leukocytosis.

Infections

Bacterial (typhoid. paratyphoid, tuberculosis, etc)
Viral (hepatitis, influenza, measles, etc)
Protozoal (malaria)

Functions of WBCs:

Neutrophil

Neutrophils defend against bacterial or fungal infection and other very small inflammatory processes that are usually first responders to microbial infection; their activity and death in large numbers forms pus.
Neutrophils are very active in phagocytosing bacteria and are present in large amount in the pus of wounds.
These cells are not able to renew their lysosomes used in digesting microbes and die after having phagocytosed a few pathogens. Most common cell seen in acute inflammation comes in and kills foreign substance.
They stick to walls of the blood vessels of the infected or injured area and prevent the entry of any foreign particles into the blood stream. They can be found in the pus of wounds.

Eosinophil

Eosinophils primarily deal with parasitic infections and an increase in them may indicate such.
Eosinophils are also the predominant inflammatory cells in allergic reactions.
The most important causes of eosinophilia include allergies such as asthma, hay fever, and hives; and also parasitic infections.
Disorder in the eosinophils may lead to over active response to a disease in the Immune system in an attempt to destroy foreign organisms

Basophil

Basophils are chiefly responsible for allergic and antigen response by releasing the chemical histamine causing inflammation.
They secrete anti coagulant and anti bodies which mediate hypersensitivity reaction within the blood. They are the reason for immediate immune reaction against external germs and diseases.

Lymphocyte

They produce antibodies against toxins secreted by bacteria and infecting germs. These antibodies will be excreted into the plasma to kill bacteria in the blood and also act as anti toxins.

The blood has three types of lymphocytes:

B cells:

B cells make antibodies that bind to pathogens to enable their destruction. (B cells not only make antibodies that bind to pathogens, but after an attack, some B cells will retain the ability to produce an antibody to serve as a 'memory' system.)

T cells:

CD4+ (helper) T cells co-ordinate the immune response and are important in the defense against intracellular bacteria. In acute HIV infection, these T cells are the main index to identify the individual's immune system activity.

CD8+ cytotoxic T cells are able to kill virus-infected and tumor cells.

Natural killer cells: Natural killer cells are able to kill cells of the body which are displaying a signal to kill them, as they have been infected by a virus or have become cancerous.

Monocyte

Monocytes share the "vacuum cleaner" (phagocytosis) function of neutrophils, but are much longer lived as they have an additional role: they present pieces of pathogens to T cells so that the pathogens may be recognized again and killed, or so that an antibody response may be mounted.
Monocytes eventually leave the bloodstream to become tissue macrophages which remove dead cell debris as well as attacking microorganisms.
Neither of these can be dealt with effectively by the neutrophils. Unlike neutrophils, monocytes are able to replace their lysosomal contents and are thought to have a much longer active life.

Leukogram

A tabulation of the leukocytes present in a blood sample.

Leukergy

The clumping of white blood cells that accompanies some inflammations and infections

Lupus Erythematosus

Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity. This is an autoimmune disease in which any part of the body may be attacked by the immune system resulting in inflammations and tissue damage.
Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs.
Four main types of lupus exist — systemic lupus erythematosus, discoid lupus erythematosus, drug-induced lupus erythematosus and neonatal lupus erythematosus. Of these, systemic lupus erythematosus is the most common and serious form of lupus.

Family Muscidae..Genus Hematobia (Horn Flies)

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These are called Horn flies.

These are smallest blood sucking flies which are responsible for the transmission of filarial worms.

There are 3 main species;

H. Irritans
H. Stimulans
H. Exigua

Host is cattle and buffalo.

Morphology:

Size of adult fly is 4mm and it is of grey color.
Several dark stripes are present on thorax.
Abdomen is dark green in color and shorter than musca.
Mouth part is projected forward and called as proboscis.
Pulps are long and stout.
Mouth part consists of Hypopharynx, Maxilla, mandibles, labium and labrum.
Flies lay egg on freshly passed feces.
Flies remain on host and leave the host when to go on another host.

Life Cycle:

Flies lay egg on freshly passed feces.
Size of egg is about 1-1.5mm.
Egg hatch immediately and larva develop.
27°C is the ideal temperature for larval development. Low temperature delays development.
From the larvae, pupa develops within 6-8 days.
From pupa, adult emerges and adult remains on the host.

Pathogenic Effects:

Flies are present in abundance on the ventral abdomen, side and back of the animal and suck blood.
When not sucking blood, these are present around the pole and cause great irritation and restlessness for animal.
Due to constant irritation, create wounds that attract other flies and result in blow fly myiasis. This also leads to secondary bacterial Infections.
These flies create Great economic losses. It is responsible for transmission of filarial worms.

Treatment & Control:

Use sprays on animal.
All of the drugs discussed previously apply on this too.
Control of these flies is very easy because these live on host.

Classification of Arthropods

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Phylum Arthropoda:

Class Insecta:

Order Diptera:

Class Arachnida:

Difference b/w Insects and Arachnids:

Classification of Viruses

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Types of virus Genomes

Forms of DNA from DNA viruses

Peplomer

Cross section of enveloped virus

Intact enveloped virus

Enveloped helical nucleocapsid

Virus Classification

It is based on following points;

Nucleic acid type
Size and morphology
Susceptibilty to chemical and physical agents
Viral enzymes
Immunological properties
Mode of replication
Mode of transmission, cell tropisms, pathogenesis and symptomatology

DNA Viruses

Parvoviridae
Papovaviridae

Papillomavirinae
Polyomavirinae

Adenoviridae
Herpesviridae
Poxviridae
Hepadnaviridae

RNA Viruses

Picornaviridae
Caliciviridae
Reoviridae
Togaviridae
Flaviviridae
Arenaviridae
Coronaviridae
Retroviridae
Bunyaviridae
Orthomyxoviridae
Paramyxoviridae
Rhabdoviridae

Bacteriophage

Bacteriophages are viruses that infect bacteria

Lytic Phage

Phage enter cell, multiply and lyse cell

Example: T phage of E. coli

Lysogenic Phage

bacteriophage integrate their nucleic acid into genome of the infected host cell (prophage)

Integration of a virus into a cellular genome is termed lysogeny

Example: lambda phage of E. coli

Introduction & History of Viruses

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The study of Viruses is called virology.

Virus Diversity

More biological diversity within viruses than in all the rest of the bacterial, plant & animal kingdoms put together
Results from the success of viruses in parasitizing all known groups of living organisms
At a molecular level, protein-protein, protein-nucleic acid, & protein-lipid interactions determine the structure of virus particles, the synthesis & expression of virus genomes & the effects of viruses on the host cell

Origin of Viruses

Three theories which seek to explain the origin of viruses:

Regressive evolution - viruses are degenerate life-forms which have lost many functions that other organisms possess & have only retained the genetic information essential to their parasitic way of life.

Cellular origins - viruses are sub-cellular, functional assemblies of macromolecules which have escaped their origins inside cells

Independent entities - viruses evolved on a parallel course to cellular organisms from the self-replicating molecules.

History of Virology

Ancient peoples were aware of the effects of virus infection
Carried out research into the causes & prevention of virus diseases
First written record of a virus infection consists of a heiroglyph from Memphis, the capital of ancient Egypt, drawn in approximately 3700BC, which depicts a temple priest called
Ruma showing typical clinical signs of paralytic poliomyelitis
The mummified body of Pharaoh Siptah (1200-1193 BC) shows that his left leg was withered and his foot was rigidly extended like a horse's hoof - classic paralytic poliomyelitis
The Pharoh Ramses V, who died in 1196BC, is believed to have succumbed to smallpox.
Smallpox was endemic in China by 1000BC. In response, the practice of variolation was developed. Recognizing that survivors of smallpox outbreaks were protected from subsequent infection, variolation involved inhalation of the dried crusts from smallpox lesions like snuff, or in later modifications, inoculation of the pus from a lesion into a scratch on the forearm of a child.
On 14th May 1796, Edward Jenner used cowpox-infected material obtained from the hand of Sarah Nemes, a milkmaid from his home village of Berkley in Gloucestershire to successfully vaccinate 8 year old James Phipps
On 1st July 1796, Jenner challenged the boy by deliberately inoculating him with material from a real case of smallpox
He did not become infected
Robert Koch & Louis Pasteur jointly proposed the 'germ theory' of disease in the 1880s that significate the importance of these organisms
Koch's postulates
The agent must be present in every case of the disease
The agent must be isolated from the host & grown in vitro
The agent must be isolated from the host & grown in vitro
The disease must be reproduced when a pure culture of the agent is inoculated into a healthy susceptible host
The same agent must be recovered once again from the experimentally infected host.
Pasteur worked extensively on rabies, which he identified as being caused by a 'virus' (from the Latin for 'poison') but he did not discriminate between bacterial & other agents of disease
On 12th February 1892, Dmitri Iwanowski, a Russian botanist, showed that extracts from diseased tobacco plants could transmit disease to other plants after passage through ceramic filters fine enough to retain the smallest known bacteria. This is generally recognized as the beginning of Virology.
In 1898, Martinus Beijerinick extended Iwanowski's results on tobacco mosaic virus & was the first to develop the modern idea of the virus, which he referred to as contagium vivum fluidum ('soluble living germ')
Also in 1898, Freidrich Loeffler & Paul Frosch showed that a similar agent was responsible for foot-and-mouth disease in cattle. Thus these new agents caused disease in animals as well as plants.
Landsteiner & Popper (1909) showed that poliomyelitis was caused by a 'filterable agent' - the first human disease to be recognized as having a viral cause
Frederick Twort (1915) & Felix d'Herelle (1917) were the first to recognize viruses which infect bacteria called bacteriophages (eaters of bacteria)
During building of the Panama Canal, yellow fever disease appeared to be spreading slowly. Through experimental transmission to mice, in 1900 Walter Reed demonstrated that yellow fever was caused by a virus, spread by mosquitoes.
1935: Wendell Stanley crystallized the tobacco mosaic virus. Suggested that viruses might be chemicals rather than tiny cells

This discovery eventually enabled Max Theiler (1937) to propagate the virus in chick embryos & successfully produced an attenuated vaccine - the 17D strain - which is still in use today
In1930s-1950s, animal systems were developing to identify & propagate many pathogenic viruses. Eukaryotic cells can be grown in vitro ('tissue culture') & viruses can be propagated in these cultures.
In recent years, an entirely new technology has been employed to study the effects on host organisms of viruses: the creation of transgenic animals & plants by means of the insertion into the DNA of the experimental organism of all or part of the virus genome, resulting in expression in the somatic cells (and sometimes in the cells of the germ line) of virus mRNA & proteins

Nature of Viruses

Sub-microscopic, obligate intracellular parasites
Produced from the assembly of pre-formed components
Virus particles (virions) themselves do not 'grow' or undergo division.
Viruses lack the genetic information which encodes apparatus necessary for the generation of metabolic energy or for protein synthesis (ribosome)
Segments of DNA or RNA wrapped in a protein coat
No metabolism
Must reproduce within cells
Vary greatly in appearance and size
Some have membrane outer surface

Structure of Viruses

Nucleic acid (genome) is DNA or RNA, but not both; it provides the information for directed cell synthesis of new virus particles
Nucleic acid is enclosed in a protein coat
Require a cell for replication (remember viruses replicate not multiply)
Rely upon cell receptors for entry to the cell
Size: in the range of 20 - 300 nm
(Size of S. aureus: ~ 1000 nm)
Genome: DNA or RNA
Genome size: in the range of 3000 - 300,000 bp
Gene number: 1 to >200

Virion Structure

Virion: a complete virus particle

Envelope: Lipid and protein membrane

Tegument: Amorphous layer between envelope and capsid

Capsid: Symmetrical protein layer around genome or core

Core: Genome and associated proteins

Viral Structure-Symmetry

Icosahedral

Constructed of 20 equilateral triangular faces e.g. foot-and mouth disease virus

Helical

Tubular construction with the subunits arranged around the nucleic acid in a coil

E.g. rabies virus

Viral Structure (no symmetry organized)

Complex

Not fully understood e.g. smallpox virus

Filamentous

Pleomorphic e.g. ebolavirus

Chemical Structure of the Genome

All DNA viruses are double stranded (except circoviruses and parvo viruses)
All DNA viruses have a single
Molecule of nucleic acid (not segmented) (most of virus is protein)
RNA viruses may be a single molecule, double stranded, or segmented and either + or – single strand

Chemical Structure-Proteins

Structural
Important for viral stability and attachment
Non-structural
Enzymes involved in viral replication
Antibodies are generally formed against the structural proteins.

What do virion proteins do?

Protect nucleic acid
Attach to receptors on cells
Penetrate cell membrane
Replicate nucleic acid (some viruses)
Begin program for replication (some viruses)

Five basic structural forms of viruses in nature

Naked icosahedral e.g. poliovirus, adenovirus, hepatitis A virus

Naked helical e.g. tobacco mosaic virus. So far no human viruses with this structure are known

Enveloped icosahedral e.g. herpes virus, yellow fever virus, rubella virus

Enveloped helical e.g. rabies virus, influenza virus, parainfluenza virus, mumps virus, measles virus

Complex e.g. poxvirus

Viral Shape

Quite varied
Helical (Rodlike or threadlike)
Isometric (Icosahedron)
Complex

Virus Structure-General Comments

Function of the outer shell (CAPSID) of a virus particle is to protect the fragile nucleic acid genome from
Physical damage - Shearing by mechanical forces
Chemical damage- UV irradiation leading to chemical modification
Enzymatic damage - Nucleases derived from dead or leaky cells or deliberately secreted by vertebrates as defence against infection
Protein subunits in a virus capsid are multiply redundant, i.e. present in many copies per particle. Damage to one subunit may render that subunit non-functional, but does not destroy the infectivity of the whole particle.

Viroids

Small (200-400nt), circular RNA molecules
Rod-like secondary structure possess no capsid or envelope
Associated with certain plant diseases
Obligate intracellular parasites

Virusoids

Satellite, viroid-like molecules, somewhat larger than viroids, dependent on the presence of virus replication for multiplication (hence 'satellite')

Prions

Rather ill-defined infectious agents
Consist of a single type of protein molecule with no nucleic acid component.
Creutzfeldt-Jakob disease in humans, scrapie in sheep & bovine spongiform encephalopathy (BSE) in cattle

Properties of Viruses

Heat sensitivity

Relative to time and a function of protein denaturation (enveloped viruses more sensitive)

pH sensitivity

Extremes are destructive

Lipid solvents

Enveloped viruses generally more sensitive

Chemicals

React with amino acids of proteins, but some inactivate DNA or RNA

Radiation and Ultraviolet light
Virus differ from other intracellular obligatory parasites

Ultramicroscopic
Unique structure
Unique replicative cycle (not binary fission)
Contain either RNA or DNA (not both)

Scope of Epidemiology-2

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Types of Epidemiological Investigations:

There are four approaches to epidemiological investigation

Descriptive epidemiology
Analytical epidemiology
Experimental epidemiology
Theoretical epidemiology

Descriptive epidemiology

Descriptive epidemiology involves observing and recording diseases and possible causal factors. “First part of an investigation” Observations may generate hypotheses that can be tested more rigorously later.

Analytical epidemiology

Analytical epidemiology is the analysis of observations using suitable diagnostic and statistical procedures.

Experimental epidemiology

Experimental epidemiologists observe and analyze data from groups of animals from which they can select, and in which they can alter, the factors associated with the groups
An important component of the experimental approach is the control of the groups
Use of laboratory animals whose short lifespan enable events to be observed more rapidly than in humans

Theoretical epidemiology

Theoretical epidemiology consists of the representation of disease using mathematical ‘models’ that attempt to simulate natural patterns of disease occurrence.

Epidemiological subdisciplines:

There are various epidemiological subdisciplines

Clinical epidemiology

Clinical epidemiology is the use of epidemiological principles, methods and findings in the care of individuals, with particular reference to diagnosis and prognosis.

Computational epidemiology

Application of computer science to epidemiological studies
Representation of disease by mathematical models
Use of expert systems (Formulating disease control strategies, predicting animals productivity Supporting management decisions)

Genetic epidemiology

Genetic epidemiology is the study of the cause, distribution and control of disease in related individuals, and of inherited defects in populations. Also explore Interactions between genetic and non-genetic factors.

Field epidemiology

Field epidemiology is a timely, judgmental process based on description, analysis, common sense and the need to design practical control policies
When outbreaks of foot-and –mouth disease occur, field epidemiologists promptly trace potential sources of infection in an attempt to limit spread of the disease.

Participatory epidemiology

1980 with development of veterinary services, animals were economically and socially important, use of local knowledge to gain information, with the main goal of improving animal health
Techniques that are employed evolved in the social science, and consist of simple visual methods and interviews to generate qualitative data
“Participatory epidemiology” it is a tool for the field epidemiologist, which is increasingly used in developing counties. Is concerned with local knowledge of, and practices relating to, the health of animals

Molecular epidemiology

Study of small genetic and antigenic differences between viruses and other microorganisms at a higher level of discrimination
The methods include peptide mapping, nucleic acid ‘fingerprinting’ and hybridization, restriction enzyme analysis, monoclonal antibodies and the polymerase chain reaction
Nucleotide sequencing of foot-and–mouth that some outbreaks of the disease involved vicinal strains, suggesting that improper inactivation or escape of virus from vaccine production plants. Unrestricted animals movement is a major factor in dissemination of the disease in West Africa.

Environmental Epidemiology:

Concerned with the relationship between disease and environmental factors such as industrial pollution and occupational hazards

Micro-Epidemiology:

Study of disease in a small group of individuals with respect to factors that influence its occurrence in larger segments of the population

Macro-Epidemiology:

Study of national patterns of disease, and the social, economic and political factors that influence them

Chronic disease epidemiology

Nutritional epidemiology

Subclinical epidemiology

Social epidemiology

Psychosocial epidemiology

Components of epidemiology:

The first stage in any investigation is the collection of relevant data. Investigations can be either qualitative or quantitative or a combination of these two approaches.

Qualitative investigations
Quantitative investigations

Qualitative investigations

The natural history of disease
The ecology of diseases, including the distribution, mode of transmission and maintenance of infectious diseases, is investigated by field observation. Field observations also may reveal information about factors that may directly or indirectly cause disease.
Causal hypothesis testing
If filed observations suggest that certain factors may be causally associated with a disease, than the association must be assessed by formulation a causal hypothesis

Quantitative investigations

Quantitative investigations involve measurement (e.g., the number of cases of disease), and therefore expression and analysis of numerical values. Quantitative investigations include surveys, monitoring and surveillance, studies, modeling, and the biological and economic evaluation of disease control. Walls of the research organization- ‘armchair epidemiology’

Surveys

A survey is an examination of an aggregate of units.
Surveys can be undertaken on a sample of the population.
A census, a cross-sectional survey records events occurring at a particular point in time.
A longitudinal survey records events over a period of time. Prospectively form the present into the future; on may be a retrospective record of past events.
In epidemiological surveys, characteristics might include the presence of particular diseases, or production parameters such as milk yield.

Screening

A particular type of diagnostic survey is screening. Identification of undiagnosed cases of disease using rapid tests or examination
Screening tests are not intended to be diagnostic; individuals with positive test results (i.e., that are classified as diseased by the screening test) usually require further investigation for definite diagnosis. They therefore differ from diagnostic tests.
Screening involves investigation of the total population (mass screening). Targeted at animals only in areas where there have been cases of disease (strategic screening). Prescriptive screening aims at early identification of diseases that can be controlled better if they are detected early in their pathogenesis.

Monitoring and surveillance

Monitoring is the making of routine observations on health, productivity and environmental factors and the recording and transmission of these observations.
Recording of milk yields or routine recording of meat inspection findings at abattoirs
Surveillance is a more intensive form of data recording than monitoring. Used to describe the tracing and observation of people who were in contact with cases of infectious disease Include all types of disease – infectious and non-infectious
It is normally part of control programmes for specific diseases.

Studies

There are four main types of epidemiological study:

Experimental studies;
Cross-sectional studies;
Case-control studies;
Cohort studies

Modelling

Using mathematical equations ‘Modelling’

Risk assessment

Evaluation of the risk of the occurrence of adverse, development of formal methods of quantitative and quantitative risk assessment e.g. Microbiological risk assessment with food safely risks, and estimation of the magnitude of microbial exposure at various stages in the production chain (rearing on the farm; transport and processing; retail and storage; preparation) to campylobacter spp and salmonella spp.

Disease control

The goal of epidemiology is to improve the veterinarian's knowledge so that diseases can be controlled effectively, and productivity thereby optimized. This can be fulfilled by treatment, prevention or eradication

Cholinergic Drugs

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Cholinergic drugs are those which release acetylcholine as neurotransmitter. These are of two types;
Cholinergic drugs which act directly on postsynaptic membrane receptors are called as direct acting drugs.
Cholinergic drugs which stop the activity of acetyl cholinesterase thus increasing the Ach in the synaptic cleft are known as indirect acting drugs.

Direct Acting Drugs

Direct acting cholinergic drugs include two types of drugs;

Natural Alkaloids… Which Include nicotine, muscarine, pilocarpine and arecoline

Synthetic Drugs… which include Acetylcholine, carbachol, methacholine and bethanicol

If an additional methyl group attaches on β carbon, methacholine is formed.

If an NH2 group is attached instead of methyl group in Acetyl choline (Acetyl co-a portion), carbachol is formed.

If a methyl group is attached on β carbon in structure of Carbachol, Bethanichol is formed.

Nicotinic receptors are only stimulated by Ach and Carbachol.
Muscarinic receptors are stimulated by all.

Prototype Drugs
Drugs which are representative of groups. These drugs are studied thoroughly and then compared with other members of the group. E.g. Ach

Effects on Different organ Systems

Therapeutic Uses

Acetylcholine

It is of no therapeutic use because it is degraded rapidly because of presence of PsuedoCholinesterase or Buterylcholinesterase in the plasma.
It Hydrolyzes Ach rapidly
Acetylcholinesterase is present in RBCs, grey matter of brain and nerve endings.
Pseudocholinesterase is also present in liver and intestine.
So, effect of Ach will not be observed intravenously or there will be short lived effect.

Methacholine

It is slowly hydrolyzed so duration of activity will be greater.
The primary clinical use of methacholine is to diagnose bronchial hyper reactivity. Which is the hallmark of asthma and also occurs in chronic obstructive pulmonary disease
This is accomplished through the bronchial challenge test, in which a subject inhales aerosolized methacholine, leading to bronchoconstriction.
Other therapeutic uses are limited by its adverse cardiovascular effects, such as bradycardia and hypotension, which arise from its function as a cholinomimetic.

Carbachol

It is not hydrolyzed by enzymes.
It increases motility of intestine and uterus.
Carbachol is a parasympathomimetic that stimulates both muscarinic and nicotinic receptors. In topical ocular and intraocular administration its principal effects are miosis and increased aqueous humour outflow. Aqueous humour is a thich watery substance filling the space b/w lens and cornea.
In the cat and rat, carbachol is well-known for its ability to induce rapid eye movement (REM) sleep when microinjected into the pontine reticular formation.
Carbachol elicits this REM sleep-like state via activation of postsynaptic muscarinic cholinergic receptors (mAChRs).

Bethanicol

Bethanechol is used clinically to treat post-op paralytic ileus (GI), urinary retention (GU) and glaucoma. (In glaucoma the choline ester, bethanechol, is used to reopen the channels while the soon to be seen adrenergics will help decrease aqueous humor production.)
It can also be used for the treatment of the gastro esophageal reflux.

Indirect Acting Drugs

These drugs are reversible or irreversible inhibitors of Acetylcholinestrase.

Reversible Inhibitors

These inhibitors block enzyme and detach from it after some time.
These include Edrophonium, Physostigmine, Neostigmine, Pyridostigmine and Carbaryl.

Irreversible Inhibitors

These block enzymes permanently but do not detach from it.
These include organophosphates (Di isopropylflourophosphate..DFP), Echothiophate, Melathion, Parathion (both are insecticides), soman, tabnum, cumaphos, trichlorofen and dichlorofen ( last 3 are used against ectoparasites).

Acetylcholinesterase

This enzyme has two reactive sites which are used for hydrolysis of compounds like Ach.
These sites are anionic and esteratic sites. Anionic site attaches to N portion of Ach and Esteratic site attaches to Carbon of Ach. So, complex is formed.
After this, addition of water occurs and acetylated Enzyme and choline detaches.
In the last step, choline detaches from esteratic site.

Edrophonium

Edrophonium first occupies anionic site and then OH covers the esteratic site and complex forms.

Its activity is short lived and again cholinesterase starts working after some time.

Because its duration of action is only about 20 minutes, edrophonium (by the so-called Tensilon test) is used to differentiate myasthenia gravis from cholinergic crisis.
In myasthenia gravis, where a person is not able to produce enough neuromuscular stimulation, edrophonium will reduce the muscle weakness by effectively supplying more acetylcholine.
In a cholinergic crisis, where a person has too much neuromuscular stimulation, edrophonium will make the muscle weakness worse by inducing a depolarizing block.

Neostigmine

When complex is formed, addition of water occurs.
Anionic site become free but esteratic site remained occupied and carbamylated enzyme is formed.
After some time, both sites become free.
Neostigmine is converted into 3-HPTA (Hydroxy phenyl trimethyl acetate) and DMCA (dimethyl carbamic Acid) during the reaction.
It is used to improve muscle tone in people with myasthenia gravis and routinely, in anesthesia at the end of an operation, to reverse the effects of non-depolarizing muscle relaxants such as rocuronium and vecuronium.
It can also be used for urinary retention resulting from general anesthesia and to treat curariform drug toxicity.
Another indication for use is the Ogilvie syndrome which is a pseudoobstruction of the colon in critically ill patients.
Historically, it has been used as a test for early pregnancy. In a non-pregnant female whose menstrual period is delayed, administration of neostigmine can provoke menstrual bleeding. Modern tests which rely on detecting hCG in urine have rendered this application obsolete.
Though one of only two treatments available for myasthenia gravis this drug is no longer available to anyone using the Medicare Part D program.

How Irreversible Inhibitors Act?

Organophosphates

DFP interacts with esteratic site and occupies it. Enzyme becomes inactive.
After some time, covalent bond if formed and it cannot be separated.
Enzyme substrate complex in this reaction is phosphorylated enzyme.
This enzyme is also called as aged enzyme and the process is called as aging of enzyme. This enzyme is long lived.
Substances which reactivate the enzyme are called reactivators of enzyme. E.g. class Oximes which include paraladoxine and obidoxine.
Paraladoxine first attaches itself to anionic site with N portion and then attaches to phosphate of DFP and separates it from Esteratic site. Then, 2-PAM itself detaches from anionic site and enzyme is free.
Reactivation can only occur before the formation of covalent bond.

Signs of organophosphate poisoning

Signs of organophosphate poisoning include:

Salivation
Lacrimation
Urinary incontinence
Defecation
GI upset/diarrhea
Emesis
miosis

Therapeutic uses of Organophosphates

Several organophosphate agents are being tried therapeutically. Cholinesterase inhibition, which in large doses makes these agents effective pesticides, also may be useful in other doses for treating dementia. Metrifonate has been used to treat schistosomiasis and is undergoing trials for the treatment of primary degenerative dementia.
The organophosphates pyridostigmine and physostigmine are carbamate anticholinesterases that have been used for many years for the treatment of myasthenia gravis. Although the short-duration anticholinesterases are generally safe, reports of their abuse are associated with a picture similar to pesticide intoxication.
One of the author's patients had been diagnosed erroneously as a myasthenic. Long-term "therapeutic" doses of physostigmine chemically altered her neuromuscular junctions to the point where she had to be slowly weaned from the drug.
Sung and others have reported on the ability of these substances to induce nicotinic receptor modulation. This explains the action of these drugs and may result in development of more effective agents.

Cholinergic Transmission

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Cholinergic transmission occurs in many steps;

Synthesis

It takes place in neurons.
Choline is taken up by active transport from outside.
Choline combines with acetyl-coA with the help of enzyme choline acetyl transferase (CAT) also called as choline acetylase. This enzyme is present inside the nerve fibers.
In this way, acetylecholine is synthesized. Hemicholinine can stop the uptake of choline.

Storage

Acetylcholine molecules are stored inside vesicles in the nerve endings.

Release

Storage vesicles empty Ach into synaptic cleft. Opening of ca channels occur and there is influx of calcium ions which help in release of Ach from the vesicles.
Drugs also work in the same way. E.g. carbachol
Some factors decrease this release. E.g. calcium deficiency

Binding

Ach binds with receptors on post-synaptic membrane and stimulates these receptors.

Removal

Ach is removed with the help of enzyme acetylcholinesterase (AchE).
Ach----------------------------------------choline + acetate.
This reaction occurs in the presence of Acetylcholinesterase.